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      Urinary N-Acetyl-β- D-Glucosaminidase and Neopterin Aid in the Diagnosis of Rejection and Acute Tubular Necrosis in Initially Nonfunctioning Kidney Grafts

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          Abstract

          Aim: The study aimed at investigating urinary neopterin, a marker of cellular immune response, and urinary N-acetyl-β- D-glucosaminidase (NAG), a marker of tubular damage, as noninvasive means to differentiate between acute tubular necrosis (ATN) and rejection in initially nonfunctioning (INF) human renal transplants. Methods: Seventy-two renal transplant patients were studied. Forty-five of them experienced an uncomplicated early posttransplant course, 27 patients suffered from INF. Twenty-two patients experienced ATN, 5 patients had a total of six biopsy-proven rejections. The NAG activity was measured by a colorimetric assay, neopterin by high-performance liquid chromatography. Receiver operating characteristics (ROC) analysis was applied to compute diagnostic performance and an optimal discriminating threshold. Results: Demographic characteristics (age, gender, cold and warm ischemia periods, HLA mismatches) and posttransplant urinary NAG and neopterin excretions did not differ between ATN and rejection groups. Both urinary NAG and neopterin excretions were lower in the control group (NAG 1.8 ± 1.0 U/mmol urinary creatinine; neopterin 270 ± 126 nmol/mmol urinary creatinine; mean ± SD) as compared with the ATN group (NAG 12 ± 10 U/mmol, p < 0.001 vs. control group; neopterin 303 ± 195 nmol/mmol, n.s.) and the rejection group (NAG 7 ± 8 U/mmol, p < 0.01; neopterin 508 ± 419 nmol/mmol, p < 0.01). The ratio of urinary neopterin to NAG excretion (uNNR; dimension nmol neopterin/U NAG activity) increased during rejections as compared with ATN (139 ± 74 vs. 50 ± 38 nmol/U, p < 0.01). The area under the ROC curve for uNNR was 0.88 ± 0.07 (p < 0.001). Applying a ROC-estimated optimal discriminator of uNNR (80 nmol/U), 16 patients with ATN and all six rejection episodes were classified correctly. Conclusion: The uNNR provides a noninvasive means to aid in the differential diagnosis of rejection and ATN in INF human renal transplants.

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          Most cited references 4

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          Immune response-associated production of neopterin. Release from macrophages primarily under control of interferon-gamma

          Neopterin, a compound derived from GTP, represents a precursor molecule of biopterin that is an essential cofactor in neurotransmitter synthesis. We have recently reported that in vivo as well as in vitro immune responses are accompanied by an increased release of neopterin and that this phenomenon can be used for the biochemical monitoring of diseases accompanied by hyperimmune stimulation. This article deals with the cellular origin and the control of this immune response- associated neopterin release in vitro. Using highly purified or monoclonal cellular reagents we demonstrate that macrophages (M phi) stimulated with supernatants from activated T cells release large amounts of neopterin into culture supernatants. Further experiments involving induction of neopterin release from M phi with various human recombinant interferons (IFNs) or neutralization of the effect of T cell supernatants with various monoclonal anti-IFN antibodies revealed immune IFN as the active principle. It thus appears that a metabolic pathway so far exclusively known in context with the generation of an essential cofactor of neurotransmitter-synthesis during immune responses is also activated in M phi under stringent control by immune IFN-like lymphokines.
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            Determination of renal clearance of neopterin by a pharmacokinetic approach.

            Pharmacokinetic modelling was used to determine the glomerular filtration rate and tubular secretion of neopterin, a marker for cellular immune activation. The method involves parameter identification employing the transient venous plasma concentration profiles of marker substances. By combined i.v. injection of neopterin and inulin which is excreted exclusively via glomerular filtration, neopterin was shown to be excreted in addition to glomerular filtration, by tubular secretion: clearance of inulin, 112 (S.D. 2.2) ml/liter; clearance of neopterin, 499 (S.D. 79.7) ml/min. A pilot experiment using in addition p-amino hippuric acid suggests that neopterin and p-amino hippuric acid may employ the same carrier system for tubular secretion.
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              Urinary and aminopeptidase N in the diagnosis of graft rejection after live donor renal transplantation

              An evaluation of the usefulness of urinary N-acetyl-beta-D-glucosaminidase (NAG) and aminopeptidase N (AAP) measurements in the diagnosis and prediction of acute and chronic renal allograft rejection was made. Enzyme activities were measured in 2,745 morning spot urine samples from 53 consecutive live donor renal allograft recipients up to 180 days after transplantation. Reference ranges of urinary enzyme activities in 14 recipients with normal graft function were higher than those established in a carefully selected group of healthy controls. 89 and 91% of 76 clinically diagnosed acute rejection episodes (ARE) in the remaining 39 graft recipients were accompanied by sharp increase over baseline of NAG and AAP respectively. All rejection episodes occurring in the early period after transplantation were characterised by high enzymuria. AAP was more sensitive than NAG as the magnitude of its increase over baseline was more, while NAG was more specific with less number of false positive elevations. Both enzymes were found to be equally good prognostic indices of graft loss and chronic graft deterioration. Regular monitoring of urinary NAG and AAP activities throughout the post transplant period would thus be valuable in (a) diagnosis and prediction of ARE in the early as well as late post operative period and (b) prediction of eventual graft outcome.
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                Author and article information

                Journal
                NEF
                Nephron
                10.1159/issn.1660-8151
                Nephron
                S. Karger AG
                1660-8151
                2235-3186
                2000
                March 2000
                08 March 2000
                : 84
                : 3
                : 228-235
                Affiliations
                aDepartment of Internal Medicine, Krankenhaus Barmherzige Brüder, Graz, andDepartments of bTransplant Surgery and cPhysiology, University of Innsbruck, Austria
                Article
                45582 Nephron 2000;84:228–235
                10.1159/000045582
                10720893
                © 2000 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 2, Tables: 3, References: 32, Pages: 8
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/45582
                Categories
                Original Paper

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